Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration
Background Immunotherapies, such as immune checkpoint inhibitors and adoptive cell therapies, have revolutionized cancer treatment and resulted in complete and durable responses in some patients. Unfortunately, most immunotherapy treated patients still fail to respond. Absence of T cell infiltration...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-09-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001224.full |
| _version_ | 1797221239251533824 |
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| author | Juan Wu Hussein Sultan Esteban Celis Andres M Salazar Valentyna I Fesenkova Aaron E Fan Diane Addis |
| author_facet | Juan Wu Hussein Sultan Esteban Celis Andres M Salazar Valentyna I Fesenkova Aaron E Fan Diane Addis |
| author_sort | Juan Wu |
| collection | DOAJ |
| description | Background Immunotherapies, such as immune checkpoint inhibitors and adoptive cell therapies, have revolutionized cancer treatment and resulted in complete and durable responses in some patients. Unfortunately, most immunotherapy treated patients still fail to respond. Absence of T cell infiltration to the tumor site is one of the major obstacles limiting immunotherapy efficacy against solid tumors. Thus, the development of strategies that enhance T cell infiltration and broaden the antitumor efficacy of immunotherapies is greatly needed.Methods We used mouse tumor models, genetically deficient mice and vascular endothelial cells (VECs) to study the requirements for T cell infiltration into tumors.Results A specific formulation of poly-IC, containing poly-lysine and carboxymethylcellulose (PICLC) facilitated the traffic and infiltration of effector CD8 T cells into the tumors that reduced tumor growth. Surprisingly, intratumoral injection of PICLC was significantly less effective in inducing tumor T cell infiltration and controlling growth of tumors as compared with systemic (intravenous or intramuscular) administration. Systemically administered PICLC, but not poly-IC stimulated tumor VECs via the double-stranded RNA cytoplasmic sensor MDA5, resulting in enhanced adhesion molecule expression and the production of type I interferon (IFN-I) and T cell recruiting chemokines. Expression of IFNαβ receptor in VECs was necessary to obtain the antitumor effects by PICLC and IFN-I was found to directly stimulate the secretion of T cell recruiting chemokines by VECs indicating that this cytokine-chemokine regulatory axis is crucial for recruiting effector T cells into the tumor parenchyma. Unexpectedly, these effects of PICLC were mostly observed in tumors and not in normal tissues.Conclusions These findings have strong implications for the improvement of all types of T cell-based immunotherapies for solid cancers. We predict that systemic administration of PICLC will improve immune checkpoint inhibitor therapy, adoptive cell therapies and therapeutic cancer vaccines. |
| first_indexed | 2024-04-24T13:02:16Z |
| format | Article |
| id | doaj.art-c91662b1da7b4c998f54e878b2bc0793 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-24T13:02:16Z |
| publishDate | 2020-09-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-c91662b1da7b4c998f54e878b2bc07932024-04-05T10:45:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-09-018210.1136/jitc-2020-001224Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltrationJuan Wu0Hussein Sultan1Esteban Celis2Andres M Salazar3Valentyna I Fesenkova4Aaron E Fan5Diane Addis6attending dermatologistּ hsultan@augusta.eduAff483 grid.410427.40000000122849329Augusta University, Georgia Cancer Center Augusta GA USAOncovir, Inc, Washington, District of Columbia, USAGeorgia Cancer Center, Augusta University Medical College of Georgia, Augusta, Georgia, USAGeorgia Cancer Center, Augusta University Medical College of Georgia, Augusta, Georgia, USAGeorgia Cancer Center, Augusta University Medical College of Georgia, Augusta, Georgia, USABackground Immunotherapies, such as immune checkpoint inhibitors and adoptive cell therapies, have revolutionized cancer treatment and resulted in complete and durable responses in some patients. Unfortunately, most immunotherapy treated patients still fail to respond. Absence of T cell infiltration to the tumor site is one of the major obstacles limiting immunotherapy efficacy against solid tumors. Thus, the development of strategies that enhance T cell infiltration and broaden the antitumor efficacy of immunotherapies is greatly needed.Methods We used mouse tumor models, genetically deficient mice and vascular endothelial cells (VECs) to study the requirements for T cell infiltration into tumors.Results A specific formulation of poly-IC, containing poly-lysine and carboxymethylcellulose (PICLC) facilitated the traffic and infiltration of effector CD8 T cells into the tumors that reduced tumor growth. Surprisingly, intratumoral injection of PICLC was significantly less effective in inducing tumor T cell infiltration and controlling growth of tumors as compared with systemic (intravenous or intramuscular) administration. Systemically administered PICLC, but not poly-IC stimulated tumor VECs via the double-stranded RNA cytoplasmic sensor MDA5, resulting in enhanced adhesion molecule expression and the production of type I interferon (IFN-I) and T cell recruiting chemokines. Expression of IFNαβ receptor in VECs was necessary to obtain the antitumor effects by PICLC and IFN-I was found to directly stimulate the secretion of T cell recruiting chemokines by VECs indicating that this cytokine-chemokine regulatory axis is crucial for recruiting effector T cells into the tumor parenchyma. Unexpectedly, these effects of PICLC were mostly observed in tumors and not in normal tissues.Conclusions These findings have strong implications for the improvement of all types of T cell-based immunotherapies for solid cancers. We predict that systemic administration of PICLC will improve immune checkpoint inhibitor therapy, adoptive cell therapies and therapeutic cancer vaccines.https://jitc.bmj.com/content/8/2/e001224.full |
| spellingShingle | Juan Wu Hussein Sultan Esteban Celis Andres M Salazar Valentyna I Fesenkova Aaron E Fan Diane Addis Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration Journal for ImmunoTherapy of Cancer |
| title | Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration |
| title_full | Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration |
| title_fullStr | Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration |
| title_full_unstemmed | Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration |
| title_short | Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration |
| title_sort | poly ic enhances the effectiveness of cancer immunotherapy by promoting t cell tumor infiltration |
| url | https://jitc.bmj.com/content/8/2/e001224.full |
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